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Synthetic Biology: Boon or Bane? Scott C. Mohr Boston University Department of Chemistry & Bioinformatics Program MIT Program on Emerging Technologies (PoET) Synthetic Biology Engineering Research Center (SynBERC). What is “synthetic biology?”.

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Synthetic Biology:Boon or Bane?Scott C. MohrBoston UniversityDepartment of Chemistry& Bioinformatics ProgramMITProgram on Emerging Technologies (PoET)Synthetic Biology Engineering Research Center (SynBERC)


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What is “synthetic biology?”

In the broadest sense, synthetic biology is the deliberate, constructive

modification of cells, organisms, populations – or their major sub-

systems – so as to achieve a human objective. It includes the artificial

creation of the natural functional components of living systems as well

as non-biological analogs, and ultimately aims to create completely

novel organisms, both biomimetic and otherwise.

“Why be content with nature’s design, arrived at by sometimes arbitrary and

now irrelevant evolutionary pressures, when a little manipulation might yield

something more useful?”

James D. Watson in DNA:The Secret of Life (2003)


What is synthetic biology l.jpg
What is “synthetic biology?”

• Colonization of molecular biology by engineers and

computer scientists?

• Genetic engineering on steroids!

• “Extreme genetic engineering.” (Etc group)

• The logical outgrowth of the scientific examination of the

living world – enabled and driven by advances in

chemistry and molecular life sciences.


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Synthetic Biology, sensu stricto

Synthetic Biology is --

“intentional engineering of biological systems...focused on the design of artificial biological systems, rather than on the understanding of natural biology...simplifying some of the complex interactions characteristic of natural biology.”

-- Synthetic Biology 1.0

International Conference

Massachusetts Institute of Technology

(June 10-12, 2004)


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Biology’s Millennium Arrives:

June 26, 2000

White House

news conference

announcing the

completion of

the rough draft

of the human

genome.


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Genome Scorecard

First “organism”: fX174 bacteriophage (1977) 5,375 nt

First bacterium: Haemophilus influenzae (1995) 1.8 Mb

First archaeon: Methanocaldococcus jannische (1996) 1.7 Mb

First eukaryote: Saccharomyces cerevisiae (1996) 12 Mb

First multicellular organism: Caenorhabditis elegans (1998) 97 Mb

First vertebrate: Homo sapiens (2000) 3 Gb

Completed Genome Sequences

APRIL 2007

Viruses: 2339

Bacteria: 446

Archaea: 37

Eukaryotes: 26

(137 in assembly; 186 in progress)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genomeprj


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Broad Institute Sequencing Capability

April 2007

Annual throughput: 60 Gb ( > all of GenBank as of 1/1/2006 !)

ABI 377 sequencers: 117

Monthly sequencing enzyme budget: $2 M

Time to sequence a typical virus genome: 4 hours

Viral genomes sequenced per week: 120

Dengue virus project: > 3300 genomes

Bacterial genomes sequenced per day: 7

Fungal genomes sequenced per day: 0.5

Facility downtime since opening in 2001: 1 day


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The Tree of Life

Charles Darwin’s notebook

entry for July 1837


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The Ultimate Archaeology

S10 – B/A Alignment

Color Scheme:

blue – polar

green – l hydrophobic

red – G, P


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Biochemical Unity

20 a-amino acids (all L-stereoisomers)

D-glucose

ATP

RNA based on A, U, G, C and D-ribose

Common metabolic pathways

etc., etc.

All living organisms share the same fundamental molecular

“operating system.”

We can assume that parts and components from one

organism will usually function within the cells of another

organism. This opens the door for major projects to

re-engineer all types of living systems.


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All presently

living species/

organisms:

Natural

Biology


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All presently

living species/

organisms:

Natural

Biology

Natural Selection

(Darwinian)

3.8 x 109 yr


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Human Selection

(Breeding)

40,000 yr (?)

Domesticated

Animals, Plants

& Fungi

All presently

living species/

organisms:

Natural

Biology

Natural Selection

(Darwinian)

3.8 x 109 yr


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“Playing God” Is

Nothing New!

Domestication has drasti-

cally altered more than 40

animal species and innu-

merable plants. We are

not strangers to altering

the biological universe –

including the environ-

ment. We continue the

rampant extermination of

vast numbers of species…


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

All presently

living species/

organisms:

Natural

Biology

Natural Selection

(Darwinian)

3.8 x 109 yr


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

All presently

living species/

organisms:

Natural

Biology

Natural Selection

(Darwinian)

3.8 x 109 yr


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

Synthetic high-Mr

Natural Products


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

Synthetic high-Mr

Natural Products

Polymers

(“plastics”)


Origins of synthetic biology in synthetic chemistry l.jpg
Origins of Synthetic Biologyin Synthetic Chemistry

  • Serendipitous synthesis of urea from ammonium cyanate by

    Friedrich Wöhler in 1828. End of élan vital and beginning of organic chemistry.

    • Natural products chemistry – isolation of organic compounds from biological sources.

    • Synthetic organic chemistry – proof of structure by synthesis

    E. Fischer, R.B. Woodward, Y. Kishi et al.

    • Rise of polymer chemistry – plastics to biopolymers.


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

Synthetic high-Mr

Natural Products

Genetically

Engineered

Cells/Vectors

Polymers

(“plastics”)

1970’s

MOLECULAR

BIOLOGY


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

Synthetic high-Mr

Natural Products

Genetically

Engineered

Cells/Vectors

Polymers

(“plastics”)

1970’s

Biopharmaceuticals, GM crops

Gene therapy

MOLECULAR

BIOLOGY


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

SYNTHETIC

BIOLOGY

Synthetic high-Mr

Natural Products

Genetically

Engineered

Cells/Vectors

~ 2000

Polymers

(“plastics”)

1970’s

GENOME

ERA

Biopharmaceuticals, GM crops

Gene therapy

MOLECULAR

BIOLOGY


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>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

SYNTHETIC

BIOLOGY

Synthetic high-Mr

Natural Products

Genetically

Engineered

Cells/Vectors

~ 2000

Polymers

(“plastics”)

Novel gene controls

New biosynthetic paths

Streamlined organisms

Utterly novel life forms?

1970’s

GENOME

ERA

Biopharmaceuticals, GM crops

Gene therapy

MOLECULAR

BIOLOGY


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Ever-enhanced Control over Living Cells

  • Random mutagenesis – followed by selection (1930s)

    • DNA sequencing & cloning – cells as protein factories

    (human insulin, 1978)

    • DNA synthesis & genetic engineering – controlled mutagenesis (1978)

    • de novo protein engineering (1990s)

    • Total synthesis of a virus genome – polio (2002),

    φX174 (2004)

    • Total synthesis of a bacterial genome (2007…?)

    • Total synthesis of a eukaryotic genome (2020??)


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Landmarks in Synthetic Biology

• Genetic Toggle (Gardner, Cantor & Collins, 2000)

  • Repressilator (Elowitz & Leibler, 2000)

  • Riboswitches (Breaker, Smolke, 2003)

  • Tunable Promoters (Mijakovic, 2005)

  • Artemesinin Pathway (Keasling, 2006)


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A Genetic Toggle Switch

Inducer 1 relieves the repression of promoter 1, allowing synthesis of

repressor 2. This blocks promoter 2 such that no more repressor 1 can

be produced. Under these conditions, promoter 2 remains off and the

reporter (GFP) does not get synthesized. As the cells grow, the pre-

existing repressor 1 gets diluted out and the repressor 2 gene is consti-

tuitively on, even in the absence of inducer 1. Adding inducer 2 releases

promoter 2, repressor 1 is generated and synthesis of repressor 2 shut

off. By the same dilution effect described above, repressor 2 gets re-

moved and the system is stably switched to the expression of the pro-

moter 2-controlled genes, including the reporter (GFP).


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Jim Collins,

Tim Gardner

Charles Cantor

Nature403, 339-342 (2000)



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The Repressilator II

Michael Elowitz

Nature403, 335-338 (2000)


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The Repressilator III

a-c sibling cells with altered phases; d cells from

different experiments; e IPTG control; f reporter-

only control


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Riboswitches

Christina Smolke


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Complexity Yields Sensitivity

E. Andrianantoandro et al. (2006) Molecular Systems Biology 2006.0028


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The Key to Conquering

Malaria: Artemisinin

Moving the biosynthesis path-

way from Artemisia annua to

yeast and E. coli promises to

cut the drug’s cost by > 90%.

Jay Keasling


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BioBricks

BioBricks is a standard for interchangable parts, developed with a view to building biological systems in living cells. The picture to the left shows BioBrick part BBa_B0034 within a plasmid. The brick is flanked by a standard BioBrick prefix (P) and suffix (S). Click the image to find out more or alternatively see:

BioBrick Standard Parts

Tom Knight

etc.

http://parts.mit.edu/registry/index.php/Main_Page


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Community Conclaves

Synthetic Biology 3.0

24th-26th June 2007

Zurich, Switzerland

http://www.syntheticbiology3.ethz.ch/

SyntheticBiology2.0

May 20-22, 2006University of California, Berkeley

Synthetic Biology 1.0

The First International Meeting on Synthetic Biology

June 10-12, 2004 at the Massachusetts Institute of Technology Cambridge, MA


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Synthetic Biology

Can Be Child’s

Play!

Nature’s first comic

book (published on

November 20, 2005)

Featuring

Bacteria Buddy,

Device Dude, and

System Sally

Downloadable at:

http://mit.edu/endy/www/

scraps/comic/AiSB.vol1.pdf


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RandyRettberg

iGEM - The international Genetically Engineered Machine

competition

iGEM is an international arena where student teams compete to

design and assemble engineered machines using advanced genetic

components and technologies.

http://parts2.mit.edu/wiki/index.php/Main_Page

http://en.wikipedia.org/wiki/IGEM


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iGEM Teams

Throng MIT’s

STATA Center

November 2006

The winning team from

Ljubljana, Slovenija de-

signed a system to inhi-

bit over-reaction of the

human innate immune

system to infection that

could lead to sepsis.

Their BioBricks function

in mammalian cells…



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CDC Select Agents* – Bacteria

• Bacillus anthracis (spores)

• Brucella abortus

• Brucella melitensis

• Brucella suis

• Burkholderia mallei

(aka Pseudomonas mallei)

• Burkholderia pseudomallei

(aka Pseudomonas pseudomallei)

• Clostridium (botulinum-

producing species)

• Coxiella burnetii

• Francisella tularensis

• Rickettsia prowazekii

• Rickettsia rickettsii

• Yersinia pestis

n = 12

* Not including agents only on USDA lists.


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CDC Select Agents* – Fungi

• Coccidiodies immitis

• Coccidiodies posadasii

n = 2

* Not including agents only on USDA lists.


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CDC Select Agents* – Viruses I

• Central European Tick-borne encephalitis

• Cercopithecine herpesvirus 1

• Crimean-Congo haemorrhagic fever

• Eastern Equine encephalitis

• Ebola

• Far Eastern Tick-borne encephalitis

• Flexal South American haemorrhagic fever

• Guanarito South American haemorrhagic fever

• Hendra

• Junin South American haemorrhagic fever

• Kyasanur Forest disease

• Lassa fever

• Marburg

* Not including agents only on USDA lists.


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CDC Select Agents* – Viruses II

• Machupo South American haemorrhagic fever

• Monkeypox

• Nipah

• Omsk haemorrhagic fever

• Reconstructed 1918 influenza

• Rift Valley fever

• Russian Spring and Summer encephalitis

• Sabia South American haemorrhagic fever

• Variola major (smallpox)

• Variola minor (alastrim)

• Venezuelan Equine encephalitis

n = 24

* Not including agents only on USDA lists.


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CDC Select Agents* – Toxins

• Abrin

• Botulinum neurotoxins

• Clostridium perfingens epsilon toxin

• Conotoxins

• Diacetoxyscirpenol

• Ricin

• Saxitoxin

• Shiga-like ribosome-inactivating proteins

• Shigatoxin

• Staphylococcal enterotoxins

• Tetrodotoxin

• T-2 toxin n = 12

* Not including agents only on USDA lists.



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Additional Potential Bioterrorism Agents

• Chlamydia psittaci

• Cryptosporidium parvum

• Escherichia coli O157:H7

• hantavirus

• Salmonella species

• Shigella species

• Vibria cholerae


Bioweapon related diseases l.jpg
Bioweapon-related Diseases

  • psittacosis

  • Q-fever

  • salmonellosis

  • shigellosis

  • smallpox

  • tularemia

  • typhoid fever

  • typhus

  • viral encephalitis

  • anthrax

  • botulism

  • brucellosis

  • cholera

  • food poisoning

  • glanders

  • hemorrhagic fever

  • lassa fever

  • melioidosis

  • plague


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“The Four Horsemen

of the Apocalypse”

by Albrecht Dűrer

(1471-1528)

war

famine

pestilence

death



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The subsurface countryside?

support network!


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Geographic details, countryside?

including the fate

of the project.


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The price of trusting countryside?

a static defense…


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“Military art finds itself placed in an equivocal position…

to renew the ancient processes of maneuver, thanks to all

that modern engines possess in the way of power, of pre-

cision, and of speed, is the task of the tacticians of our day.”


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“Military art finds itself placed in an equivocal position…

to renew the ancient processes of maneuver, thanks to all

that modern engines possess in the way of power, of pre-

cision, and of speed, is the task of the tacticians of our day.”

Charles de Gaulle

Vérs l’armee de métier

1934

(quotation borrowed from “In the valley of the shadow of death,” by Roger Brent)


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The Ideal Bioterror Weapon Would Be position…

  • contagious

  • virulent

  • robust

  • difficult to detect

  • drug-resistant

  • user-controllable


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The Ideal Bioterror Weapon Would Be position…

  • contagious

  • virulent

  • robust

  • difficult to detect

  • drug-resistant

  • user-controllable

No natural agent meets all of these criteria. Thus, sooner

or later, terrorists may decide to devise novel weapons

using the techniques of synthetic biology to enhance or

replace the characteristics of pre-existing organisms or

toxins. Countermeasures must be pursued vigorously –

in advance.


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Counter-terror Steps for Synthetic Biology position…

  • Monitor all DNA synthesis orders from all

  • suppliers worldwide.

  • Create a culture of positive achievement

  • and community solidarity among all

  • members of the SB community.

  • 3. Employ SB to develop enhanced and faster

  • methods for vaccine development.

  • Use SB to develop a range of biosensor

  • capabilities that are rapidly tuneable and

  • minimally costly.

  • 5. Launch and vigorously pursue the devel-

  • opment of SB-based antiviral therapies,

  • again stressing versatility.

  • 6. Anticipate potential terrorist strategies.


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The Promises of Synthetic Biology position…

  • Metabolic engineering on a large scale

  • a. drug synthesis

  • b. biofuel production

  • c. “green” chemical manufacturing

  • d. better GM crops (non-allergenic, drought-

  • resistant, containing more essential nutri-

  • ents, containing more cancer-inhibiting

  • compounds…

  • Sophisticated (and cheap!) sensor systems

  • Bioremediation tools

  • 4. “Attack” micro-organisms for medicine

  • 5. Combination technologies

  • a. nanobiotech

  • b. stem cell development/control


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Synthetic Biology position…

in Context

>5,000 yr

Human Selection

(Breeding)

40,000 yr (?)

Isolated high-Mr

Natural Products

~ 5,000 yr

Isolated low-Mr

Natural Products

Domesticated

Animals, Plants

& Fungi

MODERN

CHEMISTRY

All presently

living species/

organisms:

Natural

Biology

1828

Synthetic low-Mr

Natural Products

Natural Selection

(Darwinian)

3.8 x 109 yr

Drugs

~1900

2006+

SYNTHETIC

BIOLOGY

Synthetic high-Mr

Natural Products

MERGER WITH

NANOTECHNOLOGY

Genetically

Engineered

Cells/Vectors

?

~ 2000

Polymers

(“plastics”)

Novel gene controls

New biosynthetic paths

Streamlined organisms

Utterly novel life forms?

1970’s

GENOME

ERA

Biopharmaceuticals, GM crops

Gene therapy

MOLECULAR

BIOLOGY


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“Instead of just imagining the position…

world as it exists, and as we

inherit it from nature, I think

it’s becoming increasingly im-

portant that we understand

how to imagine worlds that

might be, how we would

choose how to design and

construct them.”

-- Drew Endy, MIT (2007)


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